Diastolic Heart Failure

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1 Diastolic Heart Failure Presented by: Robert Roberts, M.D., FRCPC, MACC, FAHA, FRSC Professor of Medicine and Chair ISCTR University of Arizona, College of Medicine Phoenix Scientist Emeritus and Advisor, University of Ottawa Heart Institute Past President & CEO, University of Ottawa Heart Institute Founding Director, Ruddy Canadian Cardiovascular Genetics Centre Adjunct Professor, Baylor College of Medicine Consultant to Charm Trial 2001 to 2006

2 Diastolic Heart Failure Heart failure with symptoms of pulmonary and or systemic congestion in which systolic function is preserved. The preferred designation -Heart failure with preserved left ventricular ejection fraction (HFNEF)

3 Heart Failure with preserved LVEF DIAGNOSIS Signs and symptoms of heart failure Normal or slightly abnormal systolic function (EF>50%) Abnormal diastolic LV function

4

5 Heart Failure with preserved LVEF Predisposing Factors Old age Female gender Obesity Diabetes Hypertension LV hypertrophy

6 Heart Failure with preserved LVEF Cardiac Structural Differences HFNEF has concentric remodelling SHF has eccentric HFNEF has marked myocyte hypertrophy HFNEF has distinct titin isoforms HFNEF has distinct matrix pattern Paulus et al E H J 2007,28, Borlaug et al Nature Reviews,2014,11,

7 CHARM Program 3 component trials comparing candesartan to placebo in patients with symptomatic HF CHARM- Added n=2548 LVEF 40% ACE inhibitor treated CHARM- Alternative n=2028 LVEF 40% ACE inhibitor intolerant CHARM- Preserved n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome for each trial: CV death or HF hospitalization Primary outcome for overall program: All-cause death HF, heart failure; LVEF, left ventricular ejection fraction. Pfeffer MA et al. Lancet. 2003;362:

8 CHARM-Preserved 3 component trials comparing candesartan to placebo in patients with symptomatic HF CHARM- Added n=2548 LVEF 40% ACE inhibitor treated CHARM- Alternative n=2028 LVEF 40% ACE inhibitor intolerant CHARM- Preserved n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome: CV death or HF hospitalization HF, heart failure; LVEF, left ventricular ejection fraction. Pfeffer MA et al. Lancet. 2003;362: Yusuf S et al. Lancet. 2003;362:

9 CHARM-Preserved Primary Endpoint CV death or HF hospitalization (%) % risk reduction Placebo Candesartan 366 (24.3%) 333 (22.0%) HR 0.89 (95% CI ), P=0.118 Adjusted HR 0.86, P=0.051 Number at risk: Candesartan Placebo Time (years) CI, confidence interval; HF, heart failure; HR, hazard ratio. Yusuf S et al. Lancet. 2003;362:

10 CHARM Overall Program Results by Individual Trial Cardiovascular death or hospitalization for HF Added 0.85 P=0.011 Alternative 0.77 P= Preserved Overall P=0.118 P< P for heterogeneity HF, heart failure. Pfeffer MA et al. Lancet. 2003;362: Hazard ratio

11 CHARM-Preserved Primary and Secondary Outcomes Candesartan Placebo CV death, HF hosp CV death HF hospitalization CV death, HF hosp, MI CV death, HF hosp, MI, stroke CV death, HF hosp, MI, stroke, revascularization P-value Covariate adjusted P-value Candesartan better HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Yusuf S et al. Lancet. 2003;362: HR Placebo better

12 CHARM-Preserved Investigator-Reported HF Hospitalizations Placebo Candesartan P= P=0.014 Patients (%) Number of episodes Patients hospitalized 0 Hospitalizations HF, heart failure. Yusuf S et al. Lancet. 2003;362:

13 CHARM-Preserved Development of New-Onset Diabetes Number of cases HR P-value Candesartan Placebo (CI) ( ) CI, confidence interval; HR, hazard ratio. Yusuf S et al. Lancet. 2003;362:

14 CHARM-Preserved Conclusions Candesartan reduces in hospitalizations and development of diabetes mellitus in patients with HFNEF no treatment is currently indicated for this patient population HF, heart failure; LV, left ventricular. Yusuf S et al. Lancet. 2003;362:

15 Heart Failure with preserved LVEF Familial Hypertrophic Cardiomyopathy

16 FAMILIAL HYPERTROPHIC CARDIOMYOPATHY Estimated incidence of 1 in 500 Most common cause of sudden cardiac death in the young Most common cause of sudden cardiac death in the athlete

17 Prevalence of HCM General Population 1 : ,000 USA 12,000,000 World 60,000 Canada 2,400,000 India

18 ANGIOTENSIN II BLOCKADE REVERSES MYOCARDIAL FIBROSIS IN A TRANSGENIC MOUSE MODEL OF HUMAN HYPERTROPHIC CARDIOMYOPATHY Lim D-S, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ Circulation 2001

19 Collagen Volume Fraction LOSARTAN MARKEDLY REDUCES CARDIAC FIBROSIS IN HCM MICE Transgenic Placebo Control Non- Transgenic Losartan Transgenic 4.9 3

20

21 THE TRANSGENIC RABBIT MODEL OF HCM SIMULATES HUMAN FHCM Myocyte disarray Interstitial fibrosis Ventricular dysfunction Hypertrophy

22 Simvastatin Induces Regression Of Cardiac Hypertrophy And Fibrosis And Improves Cardiac Function In A Transgenic Rabbit Model Of Human Hypertrophic Cardiomyopathy Rajnikant Patel, MD; Sherif F. Nagueh, M.D; Natalie Tsyboulev, MD; Maha Abdellatif, MD; PhD., Silvia Lutucuta, MD; Helen A. Kopelen, RDCS; Miguel A. Quinones, MD; William A. Zoghbi, MD; Mark L. Entman, MD; Robert Roberts, MD; A.J. Marian, MD. Circulation 2001: 104:r27-r34

23 Conventional Medical Therapy Beta Blockers Calcium Channel Blockers Disopyramide Amiodarone Anti-arrthyhmics Avoid Dehydration Avoid Nitroglycerine

24 Conventional Invasive Therapy ICD Septal Myectomy Surgical Alcohol ablation

25 Indications for ICD in FHCM Family History of Sudden Death Unexplained Syncope Exercise Induced Hypotension Massive Hypertrophy

26 Outflow Tract Obstruction in HCM is associated with more rapid progression of symptoms and Death Outflow Tract Obstruction is associated with a fourfold increase in progression to heart failure, death or stroke. Increase in the gradient above 30 mm Hg does not correlate with increased symptoms, death or heart failure NEJM 2003:348

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28 FHCM In Children, And Young Adults Associated With Low Mortality Receiving Contemporary Management Strategies Natural history Treatment 2.0 deaths per yr 0.5 Deaths per yr Maron et al Circulation 2016:133:62-72

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